Particles containing high concentrations of compounds available for therapeutic, diagnostic or other use are provided herein.
Effective use of potentially beneficial compounds requires the ability to deliver compositions containing useful levels of the compounds without an undue level of side effects. A variety of vehicles exist in which both hydrophilic and lipophilic compounds can be solubilized at useful levels of the compounds, and then effectively administered. However, there has heretofore been a lack of delivery vehicles in which poorly hydrophilic/poorly lipophilic compounds, such as various taxanes, vinca alkaloids, cephalosporins and steroids, can be effectively used.
One such compound is the taxane paclitaxel, a poorly hydrophilic/poorly lipophilic molecule insufficiently soluble in the more commonly used pharmaceutical carriers to make therapeutically useful compositions thereof. Rather, paclitaxel (Taxol(copyright)) is currently made available in the cremophor/ethanol vehicle Cremophor(copyright)EL. However, this composition may have certain undesirable side effects at the concentrations administered to provide effective therapeutic levels of paclitaxel, e.g., acute toxicities, exhibited in some patients to whom the composition has been administered (see, e.g., Straubinger et al., U.S. Pat. No. 5,415,869).
Straubinger et al. (see U.S. Pat. No. 5,415,869), for example, formulates paclitaxel in liposomes, and at a limited ratio of paclitaxel to liposomal lipid. Moreover, Straubinger""s maximum concentration of paclitaxel is (see Abstract) significantly below the level at which the drug is accumulated in this invention""s particles. Furthermore, Desai et al. (U.S. Pat. No. 5,439,686), Wheeler (U.S. Pat. No. 5,478,860) and Alkan-Onyuksel et al. (Pharmaceutical Res. (1994), pp. 206-212) each also encompass compounds in their vehicles at low compound:vehicle component ratios, and at concentrations less than those at which the compounds can be accumulated in the vehicles provide herein.
This invention provides a vehicle for solubilizing poorly hydrophilic/poorly lipophilic compounds, e.g., paclitaxel, such that the resulting compositions can be used to safely administer high doses of the compounds, without an undue level of side effects. This invention""s particle, which contains the compound at a high ratio of compound to other vehicle components, is neither a liposome nor an emulsion particle, and has not previously been described.
This invention provides a particle composed of a core surrounded by a hydrophilic/hydrophobic conjugate. The core comprises poorly hydrophilic/poorly lipophilic compounds for example, taxanes, vinca alkaloids, bryostatins, cyclic polypeptides such as cephalosporins, steroidal compounds, rifamycins, mitomycins, bleomycins, benzonaphthopyranone, bisintercalating antibiotics, nucleoside antibiotics, pyrrolo[1,4]benzodiazepines, macrolides, including macrolide antibiotics such as hamycin, bisindolealkaloids, camptothecins, etoposides, teniposides, DNA intercalators, antiestrogens, bis(benzimidazoles) and nucleosides such as adenine arabinoside. Such compounds have a biocompatible hydrophobic domain, e.g., an acyl chain, hydrophobic peptide or hydrophobic polymer chain, either naturally occurring therein or linked thereto by synthetic means. Alternatively the core could comprise a hydrophilic compound to which a hydrophobic domain has been conjugated such that the net result is that the core composition is poorly hydrophilic.
The conjugate surrounding the core comprises a biocompatible hydrophobic domain linked to a biocompatible hydrophilic domain. The conjugate may be a naturally occurring or synthetic molecule having a hydrophobic and hydrophilic domain or may be a conjugate of a hydrophobic and a hydrophilic domain. Suitable conjugate hydrophobic domains include, for example, the acyl chain regions of amphipathic lipids, as well as hydrophobic polymers such as silicon polymers and hydrophobic peptides. Suitable hydrophilic domains include, for example, polyethylene glycols, celluloses, hydrophilic peptides, polysaccharides, polyethylene oxides, polyacrylic acids, polyacrylamides, polyvinyl pyrrolidinones and polymethacrylates. Suitable hydrophilic domains also include the polar headgroups of amphipathic lipids; these generally are positively or negatively charged, and include phosphatidylserines, phosphatidylglycerols and phosphatidic acids, as well as other lipids, e.g., phosphatidylethanolamines, to which organic dicarboxylic acids, e.g., glutaric acid, are attached.
Preferably, the core compound is a taxane having attached thereto a 10-24 carbon-long, straight, saturated acyl chain, the conjugate hydrophobic domain is a phosphatidylethanolamine, and the conjugate hydrophilic domain is a hydrophilic polymer such as polyethylene glycol of 50-5000 molecular weight. Most preferably, the core compound is paclitaxel attached to a 12, 14 or 16 carbon-long, straight, saturated, alpha-carbon bromylated acyl chain, the conjugate hydrophilic domain is distearoyl phosphatidylethanolamine (xe2x80x9cDSPExe2x80x9d), and the conjugate hydrophilic domain is 2000 molecular weight polyethylene glycol (xe2x80x9cPEG2000xe2x80x9d).
Compositions containing such particles suspended in pharmaceutically acceptable carriers are also provided herein. These compositions can be used for highly efficient delivery of compounds to animals, i.e., for delivery at high ratios of the compounds to other components of the particles. Such delivery is also at lower toxicities than obtained with currently available formulations of similar compounds. Said high efficiency/low toxicity formulations can be used to administer agents to animals such as humans, for therapeutic, diagnostic or other purposes, e.g., for the treatment of various cancers.
Other features, objects and advantages of the invention and its preferred embodiments wll become apparent from the detailed description which follows.